info@auctorespublishing.com
+1-(302)-520-2644
+1-(302)-520-2644

The Tale of CHD4 in DNA Damage Response and Chemotherapeutic Response

  1. Home
  2. Journals
  3. Cancer Research and Cellular Therapeutics
  4. Archives
Submit Guidelines

Review Article | DOI: https://doi.org/10.31579/2640-1053/052

The Tale of CHD4 in DNA Damage Response and Chemotherapeutic Response

  • Jing Zhang 1
  • David J.H. Shih 1
  • Shiaw-Yih Lin* 1
  • 1 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

*Corresponding Author: Shiaw-Yih Lin, Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Citation: Jing Zhang, David J.H. Shih and Shiaw-Yih Lin. The Tale of CHD4 in DNA Damage Response and Chemotherapeutic Response, J. Cancer Research and Celllular Therapeutics . Doi: 10.31579/2640-1053/052

Copyright: © 2019 Shiaw-Yih Lin, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,provided the original author and source are credited.

Received: 20 June 2019 | Accepted: 07 July 2019 | Published: 08 July 2019

Keywords: CHD4; DNA damage response; mutations; chemotherapeutic response

Abstract

The chromatin remodeling factor chromodomain helicase DNA-binding protein 4 (CHD4) is a core component of the nucleosome remodeling and deacetylase (NuRD) complex. Due to its important role in DNA damage repair, CHD4 has been identified as a key determinant in cancer progression, stem cell differentiation, and T cell and B cell development. Accumulating evidence has revealed that CHD4 can function in NuRD dependent and independent manner in response to DNA damage. Mutations of CHD4 have been shown to diminish its functions, which indicates that interpretation of its mutations may provide tangible benefit for patients. The expression of CHD4 play a dual role in sensitizing cancer cells to chemotherapeutic agents, which provides new insights into the contribution of CHD4 to tumor biology and new therapeutic avenues.

Introduction

Known as Mi2β, Chromodomain helicase DNA-binding 4 (CHD4), a highly conserved protein (~250 kDa) in animals and plants [1], is one of members of the SNF2/RAD54 helicase family, which use the energy derived from ATP hydrolysis to remodel nucleosome structure [2, 3]. It comprises a core ATPase/helicase domain flanked by two Plant Homeodomain motifs (PHD fingers) that recognize modifications of histone tails, tandem chromodomains, and carboxyl-terminal domains necessary for transcriptional repression.

The ATPase domain enables CHD4 to use energy from ATP hydrolysis to remodel nucleosomes along DNA [4]. In this context, CHD4 serves as a key component of the nucleosome remodeling and deacetylase (NuRD) complex, which plays an important role in regulation of chromatin structure, gene expression, and cell cycle progression during normal development and tumorigenesis [5, 6]. In addition to CHD4, NuRD also contains a core of two lysine deacetylase proteins, HDAC1 and HDAC2, two chaperone proteins, RBBP4 and RBBP7, together with associated proteins [1, 7, 8]. It is important to point out that CHD4-NuRD complex is recruited to sites by interaction with sequence-specific DNA binding proteins, instead of recognizing specific DNA sequences [9-11]. After the interaction with DNA binding protein, the local chromatin structures are modified through nucleosomes remodeling, histone deacetylation, and promoter decommissioning [12-14]. Therefore, CHD4-NuRD complex has been identified as an integral driver of transcription.

Although CHD4 is defined as core NuRD component, increasing evidence is accumulating that CHD4 also play important NuRD-independent role in the DNA-damage response, cell cycle progression, signal transduction, and overall genome maintenance [8, 15, 16]. An early study shows that CHD4 associates with the CD4 enhancer independently of NuRD to activate CD4 expression during T-cell development[15]. In the Ikaros-deleted thymocyte system, CHD4 functions in a NuRD-independent manner to antagonize PRC2-mediated transcriptional repression [17]. In addition, the PHD fingers of CHD4 enable it to directly bind both un-methylated (H3K4) as well as K9-methylated (H3K9me3) N-terminal tails of histone H3  [18, 19]. The dual properties of CHD4 that both regulate chromatin structure via ATP hydrolysis and bind histone H3 indicate that it involves in different aspects of chromatin accessibility.  

Despite the increasing characterization of this transcriptional regulator, we still know little about the function of CHD4 in cancer progression as a DNA-repair protein. Recent studies suggest the roles CHD4 in both promoting and suppressing tumor growth [20-24]. For instance, CHD4 expression level is positively correlated with the malignant progression of non-small-cell lung cancer [25]. More recently, CHD4 expression was found to be positively correlated with metastatic stage, tumor recurrence and survival status in triple-negative breast cancer (TNBC) [21].  Interestingly, CHD4 is also implicated as a tumor suppressor in some cancer types [22]. We previously reported that CHD4 depletion and CHD4 mutations promote endometrial cancer stemness by activating TGF-beta signaling [23]. In this review, we summarized the role of this transcriptional regulator in DNA repair and its potential roles in the development of novel anti-cancer drugs.

The role of CHD4 in regulating DNA damage response

In response to DNA damage, cells initiate DNA-damage response (DDR) to prevent tumorigenesis [26-28]. The activation of DDR involves in the recruitment of DDR proteins to the damaged sites in an orchestrated manner. Increasing evidence has demonstrated that CHD4 plays an important role in genome integrity by regulating signaling and repair in response to DNA damage [29-31]. However, it is not clear whether CHD4 functions as a part of NuRD or independently of NuRD.

In response to DNA damage, CHD4 can be recruited to the sites of DNA damage by different models. One model is NuRD complex dependent, where CHD4-NuRD complex is rapidly recruited to the sites of DNA damage through the association with Poly(ADP-ribose) polymerase 1 (PARP1) [31-33]. In this model, CHD4 helps set up a transient repressive chromatin structure at sites of DNA damage to facilitate DNA repair. Another model is NuRD complex independent, where CHD4 is recruited to the sites of DNA damage by RING finger ubiquitin ligase 8 (RNF8), which promotes assembly of a subset of DNA repair factors such as RNF168 and BRCA1 at the sites of the DNA damage [16]. In addition, CHD4 can be phosphorylated by the DNA damage response kinases ATM [34, 35] and ATR [36], and in turn CHD4 can also regulate the Tip60-dependent phosphorylation of ATM [37] in response to DNA damage.

However, what is currently unknown is that whether CHD4 functions to maintain genome integrity prior to DNA damage, or it is required to repair damage upon DNA damage. For instance, CHD4 was reported to modulate the expression of RAD51, an essential protein in homologous recombination of DNA, by directly binding to the RAD51 promoter [30]. And loss of CHD4, even without the DNA damage agents, caused DNA damage in glioblastoma cells by decreasing the activity of RAD51 [30]. Interestingly, CHD4 was also shown to be recruited to DNA damage sites in poly(ADP-ribosyl)ation-dependent manner during chromatin remodeling in response to DNA damage induction [31]. Taken together, CHD4 appears to have a key role for DNA repair and cell survival through multiple mechanisms.

CHD4 and its mutations in cancer progression

Cancers with CHD4 mutations showed loss of CHD4 expression. Loss of CHD4 expression was found in over 50% of gastric and colorectal cancers [38]. In endometrial cancer, CHD4 is one of the most frequently mutated tumor suppressor genes and typically sustains missense mutations (instead of deletions) [39, 40]. Despite the highly frequent mutations of CHD4 detected, the functional significance of most CHD4 mutations is unknown. We recently showed that two point mutations of CHD4 (R975H and R1162W) in ATPase domain in endometrial cancer destabilized the CHD4 protein and consequently diminished the function of CHD4, which induces a cancer stem cell phenotype to promote cancer progression [23]. Miki Yamada et al. reported that missense single nucleotide variation p.D140E accelerated the development of cancer [41]. Therefore, interpretation of mutations in CHD4 may provide tangible benefit for patients with cancer in the near term.

In addition to its role in cancer progression, CHD4 play essential roles in stem cell differentiation [14, 42, 43], embryonic development [44, 45], striated muscle identity [46], and T cell [15] and B cell development [47, 48]. Through whole-exome sequencing and web-based gene matching, five individual de novo mutations in CHD4 were identified to cause an intellectual disability syndrome with distinctive dysmorphisms [49]. CHD4 depletion has been shown to sensitize cancer cells to some chemotherapeutic agents [23]. Therefore, these loss-of-function mutations show potential for therapeutic targeting. Together, it is important to identify CHD4 mutations that induce sensitivity to chemotherapeutic agents. A library of all clinically observed CHD4 mutations could be generated by high-throughput cloning in order to identify loss-of-function mutations that confer sensitivity to chemotherapeutic agents.

The role of CHD4 in chemotherapeutic response

CHD4 expression was found to be associated with metastatic stage, tumor recurrence and survival status, and loss of CHD4 expression sensitizes cells to DNA-damaging agents  [37, 50, 51].  We previously demonstrated the importance of CHD4 in controlling HR repair to maintain genome stability, and that deficiency in CHD4 impairs the recruitment of BRIT1 and sensitizes cells to poly (ADP-ribose) polymerase inhibitor treatment [51].  Subsequently, an siRNA screen by Carolian D’Alesio et al. identified CHD4 as a therapeutic target in colon cancer. In this study, CHD4 depletion was found to sensitize colon cancer cells to DNMT inhibitors in reactivating hypermethylated genes [52]. Later, depletion of CHD4 in acute myeloid leukemia blasts was found to sensitize cells both in vitro and in vivo to genotoxic agents daunorubicin and cytarabine [37]. More recently, CHD4 was found to mediate epithelial-mesenchymal transition in TNBC cells, and silencing of CHD4 expression in these cells increase drug sensitivity to cisplatin and PARP1 inhibitor [21].

Interestingly, CHD4 depletion in BRCA2 mutant cells promotes resistance to cisplatin by a mechanism independent of HR but dependent on RAD18 [53]. Loss of CHD4 in BRCA2 mutant PEO1 cells showed enhanced survival against the DNA-damaging agents such as the PARP inhibitor Olaparib, the double-strand break-inducing agent Zeocin, and the DNA polymerase inhibitor aphidicolin [53]. These seemingly contradictory results reveal the intricate mechanisms of CHD4 involved. To date, no therapeutic agents have been reported to exhibit selectivity towards the expression of CHD4. Therefore, CHD4 may be serve as a potential target for the development of new anti-cancer agents.

Conclusion and future directions

Recent progress in understanding the role of CHD4 in response to DNA damage, as discussed above, suggests the importance of designing effective cancer therapeutic agents that target CHD4. However, due to the crucial roles of CHD4 in both promoting and suppressing tumor growth, more knowledge of the fundamental biology downstream of CHD4 should be investigated. Identifying the binding partners of CHD4 and the signaling cascade its involved in will facilitate the generation of models revealing the biological functions of the CHD4 to cancer.

Loss-of-function mutations of CHD4 has been observed in some cancer types. Clinical genome-sequencing projects should be conducted to provide insight into the prevalence of CHD4 mutations in different cancer types and reveal patterns of these mutations. High-throughput screens of compounds associated with CHD4 and its mutations may provide new insights into the contribution of CHD4 aberrations to tumorigenesis and provide new therapeutic avenues.

In addition, the expression of CHD4 plays a dual role in sensitizing cancer cells to chemotherapeutic agents. This dual role mechanism is related to the role of CHD4 in DNA damage repair. However, it is not clear whether or not CHD4 drives resistance and how it does this. As CHD4 frequently associates with DDR proteins to regulate transcription, drugs regulating the activity or the interactions of these proteins may be a more selective approach to inhibiting undesirable CHD4 functions in cancer cells. Also post-translational modification of CHD4 can modulate its function, which offers potentially additional drug targets for novel cancer therapies.

Acknowledgements

This work was supported by a grant from the NCI (R01CA172490) to SYL.

Conflict of Interest
The author Declairs there is no Conflict of Interest.

References

  1. Denslow, S.A. and P.A. Wade, (2007) The human Mi-2/NuRD complex and gene regulation. Oncogene,. 26(37): p. 5433-8.
    View at Publisher | View at Google Scholar
  2. Seelig, H.P., et al., (1996). Two forms of the major antigenic protein of the dermatomyositis-specific Mi-2 autoantigen. Arthritis Rheum,. 39(10): p. 1769-71.
    View at Publisher | View at Google Scholar
  3. Eisen, J.A., K.S. Sweder, and P.C. Hanawalt, (1995). Evolution of the SNF2 family of proteins: subfamilies with distinct sequences and functions. Nucleic Acids Res,. 23(14): p. 2715-23.
    View at Publisher | View at Google Scholar
  4. Wang, H.B. and Y. Zhang, (2001). Mi2,an auto-antigen for dermatomyositis, is an ATP-dependent nucleosome remodeling factor. Nucleic acids research,. 29(12): p. 2517-2521.
    View at Publisher | View at Google Scholar
  5. Basta, J. and M. Rauchman, (2015). The nucleosome remodeling and deacetylase complex in development and disease. Translational research : the journal of laboratory and clinical medicine,. 165(1): p. 36-47.
    View at Publisher | View at Google Scholar
  6. Lai, A.Y. and P.A. Wade, (2011). Cancer biology and NuRD: a multifaceted chromatin remodelling complex. Nature reviews. Cancer, 11(8): p. 588-596.
    View at Publisher | View at Google Scholar
  7. O'Shaughnessy, A. and B. Hendrich, (2013). CHD4 in the DNA-damage response and cell cycle progression: not so NuRDy now. Biochemical Society Transactions,. 41: p. 777-782.
    View at Publisher | View at Google Scholar
  8. Reynolds, N., A. O'Shaughnessy, and B. Hendrich, (2013). Transcriptional repressors: multifaceted regulators of gene expression. Development,. 140(3): p. 505-512.
    View at Publisher | View at Google Scholar
  9. Fujita, N., et al., (2004). MTA3 and the Mi-2/NuRD complex regulate cell fate during B lymphocyte differentiation. Cell,. 119(1): p. 75-86.
    View at Publisher | View at Google Scholar
  10. Arenzana, T.L., H. Schjerven, and S.T. Smale, (2015). Regulation of gene expression dynamics during developmental transitions by the Ikaros transcription factor. Genes Dev,. 29(17): p. 1801-16.
    View at Publisher | View at Google Scholar
  11. Zhang, J., et al., Harnessing of the nucleosome-remodeling-deacetylase complex controls lymphocyte development and prevents leukemogenesis. Nat Immunol, 2011. 13(1): p. 86-94.
    View at Publisher | View at Google Scholar
  12. Liang, Z., et al., A high-resolution map of transcriptional repression. eLife, 2017. 6: p. e22767.
    View at Publisher | View at Google Scholar
  13. Bornelov, S., et al., The Nucleosome Remodeling and Deacetylation Complex Modulates Chromatin Structure at Sites of Active Transcription to Fine-Tune Gene Expression. Mol Cell, 2018. 71(1): p. 56-72.e4.
    View at Publisher | View at Google Scholar
  14. Yamada, T., et al., Promoter decommissioning by the NuRD chromatin remodeling complex triggers synaptic connectivity in the mammalian brain. Neuron, 2014. 83(1): p. 122-34.
    View at Publisher | View at Google Scholar
  15. Williams, C.J., et al., The Chromatin Remodeler Mi-2β Is Required for CD4 Expression and T Cell Development. Immunity, 2004. 20(6): p. 719-733.
    View at Publisher | View at Google Scholar
  16. Larsen, D.H., et al., The chromatin-remodeling factor CHD4 coordinates signaling and repair after DNA damage. Journal of Cell Biology, 2010. 190(5): p. 731-740.
    View at Publisher | View at Google Scholar
  17. Zhang, J., et al., (2011). Harnessing of the nucleosome-remodeling-deacetylase complex controls lymphocyte development and prevents leukemogenesis. Nature immunology, 2011. 13(1): p. 86-94.
    View at Publisher | View at Google Scholar
  18. Morra, R., et al., (2012). Concerted action of the PHD, chromo and motor domains regulates the human chromatin remodelling ATPase CHD4. FEBS letters,. 586(16): p. 2513-2521.
    View at Publisher | View at Google Scholar
  19. Musselman, C.A., et al.,(2012). Bivalent recognition of nucleosomes by the tandem PHD fingers of the CHD4 ATPase is required for CHD4-mediated repression. Proceedings of the National Academy of Sciences,. 109(3): p. 787-792.
    View at Publisher | View at Google Scholar
  20. Xia, L., et al., (2017). CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes. Cancer Cell,. 31(5): p. 653-668 e7.
    View at Publisher | View at Google Scholar
  21. Luo, C.W., et al.,( 2018).  CHD4-mediated loss of E-cadherin determines metastatic ability in triple negative breast cancer cells. Experimental Cell Research,. 363(1): p. 65-72.
    View at Publisher | View at Google Scholar
  22. Zhao, S., et al., (2013). Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma. Proc Natl Acad Sci U S A,. 110(8): p. 2916-21.
    View at Publisher | View at Google Scholar
  23. Li, Y., et al., (2018). CHD4 mutations promote endometrial cancer stemness by activating TGF-beta signaling. Am J Cancer Res,. 8(5): p. 903-914.
    View at Publisher | View at Google Scholar
  24. D'Alesio, C., et al.,(2016). RNAi screens identify CHD4 as an essential gene in breast cancer growth. Oncotarget,. 7(49): p. 80901-80915.
    View at Publisher | View at Google Scholar
  25. Xu, N., et al., (2016). CHD4 is associated with poor prognosis of non- small cell lung cancer patients through promoting tumor cell proliferation. European Respiratory Journal,. 48.
    View at Publisher | View at Google Scholar
  26. O'Connor, M.J., (2015).  Targeting the DNA Damage Response in Cancer. Mol Cell,. 60(4): p. 547-60.
    View at Publisher | View at Google Scholar
  27. Broustas, C.G. and H.B. Lieberman, (2014). DNA damage response genes and the development of cancer metastasis. Radiation research,. 181(2): p. 111-130.
    View at Publisher | View at Google Scholar
  28. Giglia-Mari, G., A. Zotter, and W. Vermeulen, DNA damage response. Cold Spring Harbor perspectives in biology. 3(1): p. a000745-a000745.
    View at Publisher | View at Google Scholar
  29. D'Alesio, C., et al.,(2019).  The chromodomain helicase CHD4 regulates ERBB2 signaling pathway and autophagy in ERBB2(+) breast cancer cells. Biology Open,. 8(4).
    View at Publisher | View at Google Scholar
  30. McKenzie, L.D., et al., (2019). CHD4 regulates the DNA damage response and RAD51 expression in glioblastoma. Scientific Reports,. 9.
    View at Publisher | View at Google Scholar
  31. Smith, R., et al., (2018). CHD3 and CHD4 recruitment and chromatin remodeling activity at DNA breaks is promoted by early poly(ADP-ribose)-dependent chromatin relaxation. Nucleic Acids Research,. 46(12): p. 6087-6098.
    View at Publisher | View at Google Scholar
  32. Polo, S.E., et al., (2010). Regulation of DNA-damage responses and cell-cycle progression by the chromatin remodelling factor CHD4. Embo Journal,. 29(18): p. 3130-3139.
    View at Publisher | View at Google Scholar
  33. Chou, D.M., et al., (2010). A chromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage. Proc Natl Acad Sci U S A,. 107(43): p. 18475-80.
    View at Publisher | View at Google Scholar
  34. Urquhart, A.J., et al., (2011). ATM mediated phosphorylation of CHD4 contributes to genome maintenance. Genome Integr,. 2(1): p. 1.
    View at Publisher | View at Google Scholar
  35. Polo, S.E., et al., (2010). Regulation of DNA‐damage responses and cell‐cycle progression by the chromatin remodelling factor CHD4. The EMBO Journal,. 29(18): p. 3130-3139.
    View at Publisher | View at Google Scholar
  36. Schmidt, D.R. and S.L. Schreiber., (1999). Molecular association between ATR and two components of the nucleosome remodeling and deacetylating complex, HDAC2 and CHD4. Biochemistry,. 38(44): p. 14711-7.
    View at Publisher | View at Google Scholar
  37. Sperlazza, J., et al., (2015). Depletion of the chromatin remodeler CHD4 sensitizes AML blasts to genotoxic agents and reduces tumor formation. Blood,. 126(12): p. 1462-1472.
    View at Publisher | View at Google Scholar
  38. Kim, M.S., et al., (2011). Genetic and expressional alterations of CHD genes in gastric and colorectal cancers. Histopathology,. 58(5): p. 660-8.
    View at Publisher | View at Google Scholar
  39. Kandoth, C., et al.,( 2013). Integrated genomic characterization of endometrial carcinoma. Nature,. 497(7447): p. 67-73.
    View at Publisher | View at Google Scholar
  40. Le Gallo, M., et al., (2012). Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat Genet,. 44(12): p. 1310-5.
    View at Publisher | View at Google Scholar
  41. Yamada, M., et al., (2015). Association of the Chromodomain Helicase DNA-Binding Protein 4 (CHD4) Missense Variation p.D140E with Cancer: Potential Interaction with Smoking. Genes Chromosomes & Cancer,. 54(2): p. 122-128.
    View at Publisher | View at Google Scholar
  42. Yoshida, T., et al., (2008). The role of the chromatin remodeler Mi-2beta in hematopoietic stem cell self-renewal and multilineage differentiation. Genes Dev,. 22(9): p. 1174-89.
    View at Publisher | View at Google Scholar
  43. Scimone, M.L., J. Meisel, and P.W. Reddien, (2010). The Mi-2-like Smed-CHD4 gene is required for stem cell differentiation in the planarian Schmidtea mediterranea. Development,. 137(8): p. 1231-1241.
    View at Publisher | View at Google Scholar
  44. Denner, D.R. and M. Rauchman, (2013). Mi-2/NuRD is required in renal progenitor cells during embryonic kidney development. Developmental biology,. 375(2): p. 105-116.
    View at Publisher | View at Google Scholar
  45. Hirota, A., et al., (2019). The nucleosome remodeling and deacetylase complex protein CHD4 regulates neural differentiation of mouse embryonic stem cells by down-regulating p53. Journal of Biological Chemistry,. 294(1): p. 195-209.
    View at Publisher | View at Google Scholar
  46. Gomez-Del Arco, P., et al.,(2016).  The Chromatin Remodeling Complex Chd4/NuRD Controls Striated Muscle Identity and Metabolic Homeostasis. Cell Metab,. 23(5): p. 881-92.
    View at Publisher | View at Google Scholar
  47. Yen, W.F., et al., (2019). Distinct Requirements of CHD4 during B Cell Development and Antibody Response. Cell Reports,. 27(5): p. 1472-+.
    View at Publisher | View at Google Scholar
  48. Arends, T., et al., (2019). CHD4 is essential for transcriptional repression and lineage progression in B lymphopoiesis. Proc Natl Acad Sci U S A,. 116(22): p. 10927-10936.
    View at Publisher | View at Google Scholar
  49. Weiss, K., et al., (2016). De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms. Am J Hum Genet,. 99(4): p. 934-941.
    View at Publisher | View at Google Scholar
  50. Smeenk, G., et al., (2010). The NuRD chromatin–remodeling complex regulates signaling and repair of DNA damage. The Journal of Cell Biology,. 190(5): p. 741-749.
    View at Publisher | View at Google Scholar
  51. Pan, M.R., et al., (2012). Chromodomain Helicase DNA-binding Protein 4 (CHD4) Regulates Homologous Recombination DNA Repair, and Its Deficiency Sensitizes Cells to Poly(ADP-ribose) Polymerase (PARP) Inhibitor Treatment. Journal of Biological Chemistry,. 287(9): p. 6764-6772.
    View at Publisher | View at Google Scholar
  52. Okamoto, Y., et al., (2014). An siRNA screen identifies CHD4 as a target for epigenetic therapy. Cancer Research,. 74(19).
    View at Publisher | View at Google Scholar
  53. Guillemette, S., et al., (2015). Resistance to therapy in BRCA2 mutant cells due to loss of the nucleosome remodeling factor CHD4. Genes & Development,. 29(5): p. 489-494.
    View at Publisher | View at Google Scholar

Clearly Auctoresonline and particularly Psychology and Mental Health Care Journal is dedicated to improving health care services for individuals and populations. The editorial boards' ability to efficiently recognize and share the global importance of health literacy with a variety of stakeholders. Auctoresonline publishing platform can be used to facilitate of optimal client-based services and should be added to health care professionals' repertoire of evidence-based health care resources.

img

Virginia E. Koenig

Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.

img

Delcio G Silva Junior

Journal of Women Health Care and Issues By the present mail, I want to say thank to you and tour colleagues for facilitating my published article. Specially thank you for the peer review process, support from the editorial office. I appreciate positively the quality of your journal.

img

Ziemlé Clément Méda

Journal of Clinical Research and Reports I would be very delighted to submit my testimonial regarding the reviewer board and the editorial office. The reviewer board were accurate and helpful regarding any modifications for my manuscript. And the editorial office were very helpful and supportive in contacting and monitoring with any update and offering help. It was my pleasure to contribute with your promising Journal and I am looking forward for more collaboration.

img

Mina Sherif Soliman Georgy

We would like to thank the Journal of Thoracic Disease and Cardiothoracic Surgery because of the services they provided us for our articles. The peer-review process was done in a very excellent time manner, and the opinions of the reviewers helped us to improve our manuscript further. The editorial office had an outstanding correspondence with us and guided us in many ways. During a hard time of the pandemic that is affecting every one of us tremendously, the editorial office helped us make everything easier for publishing scientific work. Hope for a more scientific relationship with your Journal.

img

Layla Shojaie

The peer-review process which consisted high quality queries on the paper. I did answer six reviewers’ questions and comments before the paper was accepted. The support from the editorial office is excellent.

img

Sing-yung Wu

Journal of Neuroscience and Neurological Surgery. I had the experience of publishing a research article recently. The whole process was simple from submission to publication. The reviewers made specific and valuable recommendations and corrections that improved the quality of my publication. I strongly recommend this Journal.

img

Orlando Villarreal

Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.

img

Katarzyna Byczkowska

Thank you most sincerely, with regard to the support you have given in relation to the reviewing process and the processing of my article entitled "Large Cell Neuroendocrine Carcinoma of The Prostate Gland: A Review and Update" for publication in your esteemed Journal, Journal of Cancer Research and Cellular Therapeutics". The editorial team has been very supportive.

img

Anthony Kodzo-Grey Venyo

Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.

img

Pedro Marques Gomes

Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.

img

Bernard Terkimbi Utoo

This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.

img

Prof Sherif W Mansour

Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.

img

Hao Jiang

As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.

img

Dr Shiming Tang

Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.

img

Raed Mualem

International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.

img

Andreas Filippaios

Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.

img

Dr Suramya Dhamija

Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.

img

Bruno Chauffert

I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!

img

Baheci Selen

"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".

img

Jesus Simal-Gandara

I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.

img

Douglas Miyazaki

We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.

img

Dr Griffith

I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.

img

Dr Tong Ming Liu

I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.

img

Husain Taha Radhi

I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.

img

S Munshi

Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.

img

Tania Munoz

“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.

img

George Varvatsoulias

Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.

img

Rui Tao

Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.

img

Khurram Arshad